?(Fig

?(Fig.5B),5B), indicating that Sm/RNP-reactive MZ B cells undergo apoptosis and removed by Rabbit polyclonal to ENO1 macrophages. M. et al., 2013). CD72c is definitely a modifier gene that regulates Faslpr-induced autoimmune disease (J. Immunol. 190: 3189C3196, 2013, Copyright? The American Association of Immunologists, Inc.). (D) Severity of the lupus-like disease in C57BL/6 (B6)-Faslpr/lpr (lpr) and MRL-Faslpr/lpr (lpr) mice shows an inverse correlation with the practical activity of CD72. The MRL background contains additional SLE-causing gene(s) other than CD72c, because mice with the MRL background show more severe disease than mice with the C57BL/6 background with the same CD72 allele. You will find polymorphisms in human being CD72, and these polymorphisms have been shown to be associated with SLE using a candidate gene analysis,23) although association of CD72 with SLE has not yet been shown by a genome-wide association study, probably because there are no known polymorphisms that substantially alter the practical activity of CD72. CD72 specifically regulates B cell reactions to Sm/RNP Although CD72 regulates the development of lupus, CD72 regulates BCR signaling only weakly when BCR is definitely polyclonally ligated using an anti-IgM antibody.22) In contrast, other inhibitory co-receptors such as CD22 and PIR-B strongly regulate BCR signaling induced by an anti-IgM antibody but only weakly regulate development of lupus.24C26) Indeed, mice deficient in CD22 or PIR-B do not develop autoimmune diseases, and develop a mild disease when combined with deficiency in other genes including Faslpr/lpr. Our recent findings on CD72-mediated signal rules explain why CD72 strongly regulates the development of lupus without regulating anti-IgM-induced BCR signaling. Previously, the inhibitory activity of CD72 was shown to be down-modulated by connection with CD100.14) However, activating ligands of CD72 were not known. We recently shown the CTLD of CD72 recognizes Sm/RNP, an RNA-related self-antigen important in the development of lupus, as mentioned above, but not additional self-antigens including DNA. This acknowledgement induces CD72-mediated transmission inhibition in B cells that create an anti-Sm/RNP antibody.27) As a result, CD72 inhibits B cell reactions to Sm/RNP but not a control antigen (Fig. ?(Fig.3A).3A). The detailed mechanism is as follows. When BCR interacts with Sm/RNP, Sm/RNP co-ligates BCR and CD72, therefore bringing CD72 into close proximity with BCR. This enables BCR-activated kinases such as Lyn to phosphorylate CD72 ITIM, leading to the recruitment of SHP-1 to CD72 (Fig. ?(Fig.3B).3B). Indeed, CD72 is definitely specifically phosphorylated and associated with SHP-1 when BCR interacts with Sm/RNP but not when BCR is definitely ligated by a control antigen. Because CD72 inhibits BCR ligation only when BCR is definitely ligated by Sm/RNP, polyclonal BCR signaling induced by anti-IgM does not look like regulated by CD72. In contrast, specific inhibition of B cell reactions to Sm/RNP mediated by CD72 may efficiently prevent the development of lupus because the immune response to Sm/RNP is essential for development of this disease. Open in a separate window Number 3. CD72 induces self-tolerance to NAs. (A) CD72 maintains self-tolerance to NAs. Among self-NAs, free NAs are rapidly degraded by nucleases after launch from deceased cells before they reach endosomes. In contrast, NAs complexed with proteins are resistant to ITK Inhibitor nucleases and are able to stimulate endosomal NAs. Antibody reactions to the complexes of DNA and proteins are non-pathogenic. The complexes of RNA and proteins such as Sm/RNP are identified by CD72. This acknowledgement inhibits activation of B cells reactive to the self-RNA/protein complexes and inhibits the production of pathogenic autoantibodies to these self-antigens. (B) Mechanisms for antigen-specific inhibition of B cells by CD72. When ITK Inhibitor B cells that express Sm/RNP-reactive BCR interact with Sm/RNP, CD72 is definitely recruited to BCR through binding to Sm/RNP. ITIM in CD72 is definitely then tyrosine-phosphorylated by BCR-associated kinases, such as Lyn, and recruits and activates SHP-1, which in turn ITK Inhibitor inactivates BCR signaling by dephosphorylating numerous signaling molecules. In B cells reactive to additional antigens, CD72 is not recruited to BCR, and is therefore unable to regulate BCR signaling. As already mentioned, CD72c is definitely a functionally fragile allele and is involved in the development of ITK Inhibitor severe lupus-like disease in MRL-Faslpr/lpr mice. SPR analysis using recombinant CD72 CTLD protein revealed the binding affinity of CD72c CTLD to Sm/RNP was weaker than that of CD72a CTLD.27) Weaker binding to Sm/RNP may make CD72c suppress.